Advanced kidney failure usually leads to anemia, primarily as a result of deficient renal erythropoietin production. There is increasing evidence that anemia is associated with the progression of left-ventricular hypertrophy, which is one of the most significant adverse risk factors in patients with chronic renal insufficiency. Left-ventricular hypertrophy predisposes to symptomatic cardiac failure and death.
Without the utilization of ESAs, lower hematocrit and hemoglobin levels have been associated with greater mortality rates for kidney failure patients on hemodialysis. It has been reported that the survival rates of patients may fall when the hematocrit falls below 30-33% [Lowrie et al., 1994]. It has also been reported that each one percent drop in hemoglobin can be associated with 14-19 percent increase in mortality [Murray et al. 1996].
These findings imply that the correction of renal anemia has the potential to improve patient prognosis. As such, most patients undergoing hemodialysis are at present treated with recombinant human erythropoietin (epoetin) to stimulate erythropoiesis to correct the anemia partially.
When erythropoietin was first approved by the US Food and Drug Administration (“FDA”) during the late 1980's for use in dialysis patients, there was no firm scientific evidence to support recommended hemoglobin levels.
Over the past 20 years, the use of erythropoiesis-stimulating agents (ESAs) has been extended throughout the ever-expanding chronic kidney disease population. However clinical practice guidelines and target hemoglobin levels outlined by the Kidney Disease Outcomes Quality Initiative (“KDOQI”) guidelines [NKF-KDOQI Work Group, 1997], which drive clinical practice, are still largely based on observational data. In 1997, the dialysis outcome and quality initiative (“DOQI”) in the US recommended a target hematocrit range of 33-36% and hemoglobin targets of 11-12 g/dL [NKF-DOQI Work Group, 1997].
Based on the observational data, there has been a consensus building in the nephrology community that raising hemoglobin levels in chronic kidney disease patients is beneficial. These attitudes are based on observed improvements in quality-of-life parameters such as exercise tolerance and neurological function. The consensus was developed from a physiologic perspective that the higher hemoglobin targets for anemic patients reflected a normalization of hematocrit levels which would be associated with better outcomes among the anemic.
Hematocrit is the percentage of red blood cells in a blood sample volume. Hemoglobin is the oxygen-carrying molecule within red blood cells. Both are utilized as markers for the oxygen deliverability of a patient's blood. In general, adult males with a hematocrit of less than 41% and adult females with a hematocrit of less than 36% are considered anemic. The amount of hemoglobin in the blood is typically expressed in g/dL of blood (grams of hemoglobin per deciliter). The World Health Organization defines anemia as hemoglobin less than 12 g/dL for nonpregnant women and less than 13 g/dL for men.
Following the FDA approval of erythropoiesis-stimulating agents for use in the treatment of anemia associated with chronic renal failure (“CRF”), data from randomized, controlled clinical studies [Besarab et al. 1998, Singh et al. 2006, Drueke et al. 2006] showed increased rates of death and serious cardiovascular events when erythropoiesis-stimulating agents were administered for the purpose of achieving a higher hemoglobin concentration relative to a lower concentration.
Research performed by Besarab et al. [1998] was published as the Normal Hematocrit Study and rigorously tested the potential therapeutic advantages of higher hematocrit levels in certain dialysis patients. The Normal Hematocrit Study had a total of 1,265 patients with chronic renal disease on maintenance epoetin alfa, an ESA, with a hematocrit of 30±3% who were enrolled and randomized into group A (treatment group) or group B (control group). Group A patients received additional epoetin alfa during a correction phase to “normalize their hematocrit” to 42±3%, while patients in control group (B) remained on maintenance epoetin alfa (hematocrit: 30±3%). The primary objective of the study was to assess the effects of two different hematocrit target levels, 42% and 30%, on mortality and morbidity in hemodialysis patients with documented clinically evident cardiac disease [congestive heart failure (CHF) or ischemic heart disease] who were receiving epoetin alfa therapy. The primary endpoint was time-to-death or first non-fatal myocardial infarction. The final results of the study disclosed (Table 1 and FIG. 1) that dialysis patients normalized to a hematocrit of 42% (“normal hematocrit”) experienced higher mortality and more non-fatal myocardial infarctions than patients targeting a hematocrit of 30%. The study was terminated early due to the detection of important safety considerations.
TABLE 1Normal Hematocrit Primary Endpoint Components: Final Study ReportHigh HctLow HctComponentn = 634n = 631Primary endpoint deaths208 (32.8%)173 (27.4%)Total deaths221 (34.9%)185 (29.0%)Non-fatal MI20 (3.2%)16 (2.5%)Hct = hematocrit
The CHOIR (Correction of Hemoglobin and Outcomes In Renal insufficiency) study [Singh et al. 2006] was conducted with the objective of comparing the composite cardiovascular event rates for chronic renal failure patients randomized into the following two groups: those having a target hemoglobin of 13.5 g/dL (group A; high hemoglobin group) versus those having a target hemoglobin of 11.3 g/dL (group B; low hemoglobin group). The hypothesis of the study was that in patients with chronic kidney disease, the use of recombinant human erythropoietin (epoetin alfa), an ESA, to achieve a higher hemoglobin level (13.5 g per deciliter) would decrease the risk of complications from cardiovascular causes and death, as compared with a lower hemoglobin level (11.3 g per deciliter). The physiologic approach of the working hypothesis was that higher hematocrit reflected a higher rate of perfusion of erythrocytes and improved oxygen delivery, metabolism and overall health. The primary efficacy outcome variable was a comparison of time-to-events for a composite primary endpoint integrating the following: mortality (all-cause mortality), CHF hospitalization (not including hospitalizations during which renal replacement therapy occurred), non-fatal stroke, and non-fatal myocardial infarction. Overall, 1432 patients were enrolled and randomized—715 to the higher hemoglobin group and 717 to the lower hemoglobin group. The study's primary endpoint showed a statistically significant disadvantage for patients in the higher hemoglobin group. Specifically, primary endpoint events occurred among 125 (17.5%) of patients in the higher hemoglobin group and 97 (13.5%) of patients in the lower hemoglobin group. Like the Normal Hematocrit Study, the CHOIR study was terminated before completion because the safety monitoring board determined that the study had little or no chance to demonstrate a benefit in the higher hemoglobin group. Baseline characteristics were generally similar between the two study groups, with the most common etiologies of renal failure relating to diabetes or hypertension. The time-to-event curves for the primary endpoint are shown in FIG. 2.
The CREATE (“Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin beta trial”) study [Drueke et al. 2006], a third important study, was designed and conducted with parametric features similar to the CHOIR study. Specifically, the CREATE study randomized patients who were not undergoing dialysis to either a high hemoglobin target or a low hemoglobin target and also used a time-to-event analysis for a primary composite cardiovascular endpoint. In CREATE, 603 patients were randomized to a high hemoglobin target (13 to 15 g/dL) or a low hemoglobin target (10.5 to 11.5 g/dL). The primary endpoint was a composite of eight cardiovascular events: sudden death, myocardial infarction, acute heart failure, stroke, transient ischemic attack, angina pectoris resulting in hospitalization for 24 hours or more or prolongation of hospitalization, complication of peripheral vascular disease (amputation or necrosis), or cardiac arrhythmia resulting in hospitalization for 24 hours or more. Overall, a primary endpoint event occurred in 58 of 301 (19.3%) patients in the high hemoglobin group and 47 of 302 (15.6%) patients in the low hemoglobin group. Dialysis was required in more patients in the high hemoglobin group than in the low hemoglobin group (127 versus 111).
Potential adverse effects of anemia correction may be related to the increase in hemoconcentration as a result of fluid removal during dialysis. Hemoconcentration would effect rises in hematocrit and hemoglobin. As a relatively higher hemoglobin target level is associated with cardiac event risk, it is critical to be able to determine the optimum dose of erythropoiesis-stimulating agents for maximum benefit and minimum risk within the hemoconcentration framework.